Dosage form for delivering acetaminophen or phenylpropanolamine

ABSTRACT

A dosage form is disclosed comprising a wall that surrounds a compartment with an exit means in the wall. The compartment comprises a first or fast releasing lamina and a second or short releasing lamina that are delivered through the exit means over two different periods of time.

CROSS REFERENCE TO CO-PENDING APPLICATION(S)

This application is a continuation of U. S. patent application Ser. No.07/092,857 filed Sept. 3, 1987, now U.S. Pat. No. 4,814,181 issued Mar.21, 1989 and is co-pending with U. S. patent application Ser. No.07/034,971 filed Apr. 6, 1987 now U. S. Pat. No. 4,786,503 issued Nov.22, 1988, and co-pending U.S. patent application Ser. No. 07/313,006filed Feb. 21, 1989. All the applications are assigned of record to ALZACorporation of Palo Alto, Calif.

FIELD OF THE INVENTION

This invention pertains to both a novel and useful dosage form fordelivering a beneficial agent to an environment of use. Moreparticularly, the invention relates to a dosage form comprising a wallthat surrounds a compartment. The compartment comprises a first laminacomprising a beneficial agent that is delivered in a short period oftime, and a second lamina comprising a beneficial agent that isdelivered in a prolonged period of time. At least one passagewaythorough the wall permits delivery of the first lamina comprising itsbeneficial agent and delivery of the second lamina comprising itsbeneficial agent to an environment of use.

BACKGROUND OF THE INVENTION

Since the beginning of antiquity those engaged in pharmacy and medicinehave sought a dosage form designed as a delivery system for thecontrolled administration of a beneficial agent to an environment ofuse. The first written reference to a delivery system, a dosage form, isin the Eber Papayrus written about 1552 B. C. The Eber Papayrus mentionsdosage forms such as anal suppositories, vaginal pessaries, ointments,oral pill formulations and other dosage preparations. About 2500 yearspassed without any advance in dosage form development until the Arabphysician Rhazes, 865-925 A. D., invented the coated pill. About acentury later the Persian Avicenna, 980-1037 A. D., coated pills withgold or silver for increasing patient acceptability and for enhancingthe effectiveness of the drug. Also around this time the first tabletwas described in Arabian manuscripts written by Al-Zahrawi, 936-1009 A.D. The manuscripts described a tablet formed from the hollow impressionsin two matched, facing tablet molds. Pharmacy and medicine waited about800 years for the next innovation in dosage forms when in 1883 Mothesinvented the capsule for administering a drug. The next quantum andprofound leap in dosage forms came in 1972 with the invention of theosmotic delivery device invented by Theeuwes and Higuchi. This uniqueosmotic delivery device is manufactured in one embodiment for oral use.In this embodiment, it embraces the appearance of a tables comprising aninternal drug core and a delivery portal. After a start-up period, itdelivers drug at a controlled rate over a prolonged period of time. Itis the first oral dosage form that delivers a drug throughout the entiregastrointestinal tract in a controlled dose per unit time.

While the above described osmotic system comprising a single drug corerepresents an outstanding and pioneering advancement in the osmoticdelivery art, and while the osmotic system is useful for dispensinginnumerable drugs to the environment of use, it has now been

ARC 1393 discovered that these osmotic systems can be improved furtherto enhance the delivery kinetics and the usefulness of the osmoticsystems. That is, it now has been unexpectedly discovered that a noveldosage form manufactured as an osmotic device can be provided to delivera bio-affecting drug at a fast rate and deliver a bio-affecting drug ata slow rate in a substantially constant dose over a prolonged period oftime. By providing a fast rate of delivery the dosage form makes drugavailable early in the delivery period and essentially eliminates thestart-up time associated with the prior art osmotic dosage forms. Thedosage form by providing a slow rate of delivery also makes availabledrug delivery at a controlled and constant rate over a prolonged periodof time. The dosage form made available by this invention uniquelyembodies delivery at two different rates, thereby functioning accordingto a pre-selected, built-in optimal program of drug presentation.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation it is an immediate objectof this invention to provide an improved dosage form, manufactured as anosmotic delivery device, for the controlled delivery of a drug at a fastrate and at a slow and constant, prolonged rate to a drug receptor forproducing a therapeutic effect.

Another object of the invention is to provide an osmotic dosage formthat comprises means for delivering a beneficial agent instantly,thereby overcoming the start-up time known to the prior art.

Another object of the invention is to provide an osmotic dosage formthat comprises means for instantly delivering a beneficial agentfollowed by delivering a beneficial agent over a prolonged period oftime.

Another object of the invention is to provide an osmotic dosage formcomprising means for the concurrent and instant delivery of a beneficialagent and for delivery of a beneficial agent at a slow rate over aprolonged period of time.

Another object of the invention is to provide an osmotic dosage formcomprising a wall that surrounds a compartment which compartmentcomprises means for providing a beneficial drug at a fast delivery rateand means for delivering a beneficial drug at a slow rate over time.

Another object of the invention is to provide an osmotic dosage formcomprising a wall that surrounds a compartment, which compartmentcontains a drug that is available for immediate delivery forsubstantially eliminating the start-up time associated previously withosmotic dosage forms.

Another object of the invention is to provide an osmotic dosage formcomprising a first lamina comprising a drug and a releasable binder,which lamina delivers drug immediately for increasing the period of timedrug is available for performing its beneficial effects.

Another object of the invention is to provide an osmotic dosage formcomprising a first delivery lamina that contains a drug and a releasablebinder that delivers drug immediately, and a slow delivery second laminathat contains a drug and preferably a different releasable binder thatdelivers the drug at a slower rate over a prolonged period of time.

Another object of the present invention is to provide a dosage formcomprising a beneficial drug that can be from insoluble to very solublein an aqueous fluid, and which drug can be delivered by the dosage format two different rates of drug delivery.

Another object of this invention is to provide a dosage form that canadminister to a warm-blooded host a complete pharmaceutical regimencomprising poorly soluble drugs to very soluble drugs that are madeavailable immediately and also at a controlled and continuous rate for aprolonged particular time period, the use of which requires interventiononly for initiation and possible termination of the therapeutic regimen.

Another object of the present invention is to provide a dosage form fordelivering a drug in the gastrointestinal tract that substantiallyavoids a premature break-up and undergoes a change in its drug deliveryrate from a fast to a slower rate of drug delivery over a prolongedperiod of time of at least eight hours.

Another object of the invention is to provide a laminae comprising afast drug releasing lamina in laminar arrangement with a slow drugreleasing lamina which laminae comprise a water soluble composition forreleasing a drug in the laminae in the presence of water or in abiological fluid that enters the laminae.

Another object of the invention is to provide an oral, osmotic devicethat dispenses a drug at a fast rate followed by release of drug at aslow rate, which rates in either instance are controlled by the osmoticdevice.

Other objects, features and advantages of the invention will be moreapparent to those skilled in the dispensing art from the followingdetailed specification, taken in conjunction with the drawing figuresand the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawing figures, which are not drawn to scale, but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows.

FIG. 1 is a side, elevated view of a dosage form provided by thisinvention designed and shaped for oral administration to thegastrointestinal tract of an animal, the dosage form comprising twodistinct lamina comprising a beneficial drug in each lamina;

FIG. 2 is an opened view of the dosage form of FIG. 1 for illustratingthe internal structure of the dosage form;

FIG. 3 is a graph depicting the amount of beneficial agent delivered indifferent agent receiving environments;

FIG. 4 is a graph depicting the amount of beneficial agent delivered indifferent agent receiving environments with the dosage form comprisingdifferent exit means;

FIG. 5 is a graph depicting the total amount of beneficial agentdelivered over a prolonged period of time;

FIG. 6 is a graph depicting the amount of beneficial agent deliveredthrough exit means of different dimensions; and,

FIG. 7 is a graph depicting the effect of the weight of the wall on theamount of beneficial agent delivered from dosage forms; In the drawingsand in the specification like parts in related figures are identified bylike numbers. The terms appearing earlier in the specification and inthe drawings, as well as embodiments thereof, are further describedelsewhere in this specification.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawing figures in detail, which drawing FIGURES arean example of the dosage forms provided by this invention, and whichexamples are not to be construed as limiting, one example of this dosageform is illustrated in FIG. 1 designated by the numeral 10. In FIG. 1,dosage form 10 is manufactured as an oral device comprising a body 11.Dosage form 10 comprising body 11 can be shaped, sized, adapted andstructured for easy placement and prolonged reaction in a biologicalenvironment of use for the controlled delivery of a beneficial agentthereto. Dosage form 10 comprises wall 12 with a passageway 13 forconnecting the inside of the dosage form 10 with the exterior of thedosage form.

In FIG. 2, dosage form 10 is seen in opened section. In FIG. 2, dosageform 10 comprises body 11 having a wall 12. Wall 12 surrounds and formsan internal compartment. Wall 12 is opened at 14 for illustratinginternal compartment 15. Wall 12 comprises in at least a part asemipermeable composition that is permeable to the passage of anexterior fluid present in the environment of use, and it issubstantially impermeable to the passage of a beneficial agent and otheringredients that may be present in compartment 15. Wall 12 of dosageform 10 is substantially inert, that is it maintains its physical andchemical integrity during the dispensing of a beneficial agent, and itis formed of a non-toxic composition. Dosage form 10, as seen in FIG. 1and FIG. 2, can be made of any conventional geometric shape such as anellipsoid, or bean shaped, circular shaped, rectangular shaped, capletshaped and the like.

In FIG. 2, dosage form 10 comprises in compartment 15 a first lamina 16and a second lamina 17. First lamina 16 and second lamina 17 are incontacting arrangement and they function in concert for providing acomplete beneficial delivery program. First lamina 16 comprises abeneficial agent 18, preferably a beneficial drug, and second lamina 17comprises a beneficial agent 19, such as a drug.

First lamina 16 comprising beneficial agent 18 is a fast releasinglamina. The phrase, "fast releasing lamina", as used for the purpose ofthis invention, generically denotes that when dosage form 10 is inoperation in the environment of use fast releasing lamina 16 is releasedfrom dosage form 10 during the first hours of operation. Fast releasinglamina 16 is dispensed by, for example, going into solution or forming adispensable semi-viscous carrier almost immediately and it deliversbeneficial agent 18 almost immediately to a fluid biological environmentof use. The release of fast dissolving lamina 16 with beneficial agent18 overcomes a delayed start-up time in agent delivery, thereby whenbeneficial agent 18 is a drug, it is made available to produce earlyplasma concentrations of drug in a therapeutic program in a warm-bloodedanimal, including humans.

In a presently preferred embodiment fast releasing lamina 16 comprises ahydroxypropylcellulose and other lamina 16 forming components such ashydroxypropylmethylcellulose, polyvinyl pyrrolidone, an effervescentagent such as sodium bicarbonate, potassium bicarbonate, and the like, abuffer such as sodium acetate, potassium acetate and the like, abeneficial agent, and the like. The hydroxypropyl-cellulose used for thepurpose of this invention is a nonionic ether with a neutral pH rangeand a hydroxypropyl content of 7% to 16%. More specifichydroxypropylcelluloses comprising a hydroxypropyl content of 7% to 10%,a hydroxypropyl content of 10% to 13%, and a hydroxypropyl content of13% to 16%. In the embodiments wherein lamina 16 comprises ahydroxypropylmethylcellulose, the hydroxypropylmethylcellulosepreferably comprises a hydroxypropyl content of 4% to 12% and amethyloxy content of 19% to 24%. Exemplary hyroxypropylmethylcellulosesthat can be used for forming lamina 16 comprises a member selected fromthe group consisting of (a) a hydroxypropylmethylcellulose having adegree of polymerization (DP) of about 50, a viscosisty of about 3centipoises measured as a 2% solution in water, and a number averagemolecular weight of about 9,200; (b) a hydroxypropylmethylcelluloseexhibiting a viscosity of about 3 centipoises, a degree ofpolymerization of about 51, and a number average molecular weight ofabout 9,600; (c) a hydroxypropylmethylcellulose having a viscosity of 5,a degree of polymerization of 56, and a number average molecular weightof 11,300; (d) a hydroxypropylmethylcellulose having a viscosity of 15,a degree of polymerization of 79 and a number average molecular weightof 15,900; and (e) a hydroxypropylmethylcellulose having a viscosity of35, a degree of polymerization of 102 and a number average molecularweight of 19,600. Generally a hydroxypropylmethylcellulose used forforming fast releasing lamina 16 will comprise a number averagemolecular weight of about 9,000 to 25,000. Fast releasing lamina 16generally comprises about 5% to 50% of hydroxypropylcellulose, and 2% to15% of hydroxypropylmethylcellulose. Fast releasing lamina 16 in anotherpreferred embodiment can comprise a binder such as polyvinylpyrrolidone,lightly cross-linked polyvinylpyrrolidone, and the like.

The expression, "slow releasing lamina 17" as used herein denotes lamina17 is released through passageway 13 at a controlled and continuous rateof 11/2 hours to 14 hours or longer. The period of time in somepreferred embodiments generally is from 2 hours to 12 hours. Slowreleasing lamina 17 comprising beneficial agent 19 releases beneficialagent 19 over a corresponding period of time to the environment of use.

Lamina 17 in a presently preferred manufacture comprises a hydrogel, acellulosic polymer and a beneficial agent. Representative hydrogelcomprise a polyalkylene oxide. The polyalkylene oxide can include ahomopolymer of ethylene oxide, propylene oxide and butylene oxide, andcopolymers of ethylene oxide, propylene oxide and butylene oxide. Thepolyalkylene oxides used herein generally have an average molecularweight of about 10,000 to 5,000,000 and in a presently preferredembodiment an average molecular weight of 10,000 to 900,000. The degreeof polymerization is about 200 to 115,000. The presently preferredpolyalkylene oxide is polyethylene oxide exhibiting a number averagemolecular weight of 10,000 to 200,000. Polyalkylene oxides are known tothe art in U. S. Pat. Nos. 3,963,805 and 4,211,681.

In a presently preferred embodiment the cellulosic polymer used formanufacturing lamina 17 comprise a hydroxypropylmethylcellulose having anumber average molecular weight of from 9,000 to 250,000. Thehydroxypropylmethylcellulose present in slow releasing lamina 17 can bethe same or different than the hydroxypropylmethylcellulose present infast releasing lamina 16. In a presently preferred proviso lamina 17differs from lamina 16 wherein lamina 16 compriseshydroxypropylcellulose.

Representative hydroxypropylmethylcellulose polymers useful for themanufacture of slow releasing lamina 17 comprises (a)hydroxypropylmethylcellulose exhibiting a viscosity of 3, a degree ofpolymerization of 48 and a number average molecular weight of 9,200; (b)hydroxypropylmethylcellulose exhibiting a viscosity of 35, a degree ofpolymerization of 102 and a number average molecular weight of 19,600;(c) a hydroxypropylmethylcellulose having a viscosity of 100, a degreeof polymerization of 145 and a number average molecular weight of27,800, (d) a hydroxypropylmethylcellulose having a viscosity of 4,000,a degree of polymerization of 460 and a number average molecular weightof 88,300; (e) a hydroxypropylmethylcellulose having a viscosity of15,000, a degree of polymerization of 690 and a number average molecularweight of 132,500; (f) a hydroxypropylmethylcellulose exhibiting aviscosity of 100,000, a degree of polymerization of 1,260 and a numberaverage molecular weight of 241,900 and the like. Lamina 17 in anotherembodiment comprises the cellulose polymer carboxymethylcellulose, suchas sodium carboxymethylcellulose.

Wall 12 of dosage form 10 comprises neat, or at least in part, asemipermeable wall forming composition that does not adversely affectthe beneficial agent, an animal host and other components comprisingdosage form 10. Wall 12 is permeable to the passage of an external fluidpresent in the environment of use such as water and biological fluids,and wall 12 is substantially impermeable to the passage of beneficialagents and other components comprising dosage form 10. The selectivelysemipermeable materials useful for manufacturing wall 12 are, in apresently preferred embodiment, non-erodible and they are insoluble influids. Typical polymeric materials for forming wall 12 comprise amember selected from the group consisting of cellulose esters, celluloseethers and cellulose ester-ethers. The cellulosic polymers have a degreeof substitution, D.S., on their anhydroglucose unit from greater than 0up to 3, inclusive. By degree of substitution is meant the averagenumber of hydroxyl groups originally present on the anhydroglucose unitcomprising the cellulose polymer that are replaced by a substitutinggroup. Representative polymeric materials include a member selected fromthe group consisting of cellulose acylate, cellulose diacylate,cellulose triacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tri-cellulose alkanylates, mono-, di- andtri-cellulose aroylates, and the like. Exemplary polymers includecellulose acetate having a D.S. up to 1 and an acetyl content up to 21%;cellulose acetate having an acetyl content of 32 to 39.8%; cellulosediacetate having a D.S. of 1 to 2 and an acetyl content of 21% to 35%;cellulose triacetate having a D.S. of 2 to 3 and an acetyl content of35% to 44.85; and the like. Examples of more specific cellulose polymersinclude cellulose propionate having a D.S. of 1.8 and a propionylcontent of 39.2% to 45% and a hydroxyl content of 2.8% to 5.4%;cellulose acetate-butyrate having a D.S. of 1.8 and an acetyl content of13% to 15% and a butyryl content of 34% to 39%; cellulose acetatebutyrate having an acetyl content of 2% to 29%, a butyryl content of 17%to 53% and a hydroxyl content of 0.5% to 4.7%; cellulose triacylateshaving a D.S. of 2.9 to 3 such as cellulose trivalerate, cellulosetrilaurate, cellulose tripalmitate, cellulose trisuccinate, andcellulose trioctanoate; cellulose diacylates having a D.S. of 2.2 to 2.6such as cellulose disuccinate, cellulose dipalmitate, cellulosedioctanoate, cellulose dipentate, and the like. Additional semipermeablepolymers that can be used for manufacturing wall 12 include acetaldehydedimethyl acetate, cellulose acetate ethylcarbamate, cellulose acetatephthalate for use in environments having a low pH, cellulose acetatemethyl carbamate, cellulose acetate dimethylaminoacetate, semipermeablepolyamides, semipermeable polyurethanes, semipermeable sulfonatedpolystyrenes, cross-linked selective semipermeable polymers formed bythe coprecipitation of a polyanion and a polycation as disclosed in U.S. Pats. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006; and 3,546,142;semipermeable polymers as disclosed by Loeb and Sourirajan in U. S. Pat.No. 3,133,132; lightly cross-linked plasticized polystyrene derivatives;cross-linked poly(sodium styrene sulfonate); crosslinkedpoly(vinylbenzyltrimethyl ammonium chloride); semipermeable 1 polymersexhibiting a fluid permeability of 10⁻⁵ to 10⁻¹ (cc . mil/cm² hr.atm)expressed as per atmosphere of hydrostatic or osmotic pressuredifference across the semipermeable wall. The polymers are known to theart in U. S. Pat. Nos. 3,845,770; 3,916,889; and 4,160,020; and inHandbook of Common Polymers by Scott, J. R. and Roff, W. J., (1971)published by CC Press, Cleveland, Ohio.

Dosage form 10 comprises a beneficial agent 18 in fast releasing lamina16 and a beneficial agent 19 in slow releasing lamina 17. The beneficialagent can be the same in both lamina, or the beneficial agent can bedifferent in both lamina. The expression, "beneficial agent", as usedherein, in a preferred embodiment, denotes a drug. In the presentspecification and claims the term, "drug" includes any physiologicallyor pharmacologically active substance that produces a local or systemiceffect in animals, including warm-blooded mammals, humans and primates;avians; household, sport and farm animals; laboratory animals; fishes;reptiles; and zoo animals. The term, "physiologically", as used herein,denotes the administration of a drug to produce generally normal levelsand functions in a warmblooded animal. The term, "pharmacologically"generally denotes variations in response to the amount of drugadministered to the host. See Stedman's Medical Dictionary, (1966)published by Williams and Wilkins, Baltimore, Md.

The beneficial drug that can be delivered by the dosage form includesinorganic and organic compounds without limitation, including drugs thatact on the peripheral nerve, adrenergic receptors, cholinergicreceptors, nervous system, skeletal muscles, cardiovascular system,smooth muscles, blood circulatory system, synaptic sites, neuroeffectorjunctional sites, endocrine system, hormone systems, immunologicalsystem, organ systems, reproductive system, skeletal system, autocoidsystems, alimentary and excretory systems, inhibitors of autocoids, andhistamine systems. The therapeutic drug that can be delivered for actingon these recipients include anticonvulsants, analgesics,anti-Parkinsons, anti-inflammatories, anesthetics, antimicrobials,anti-malarials, antiparasitic, antihypertensives, angiotensin convertingenzyme inhibitor, antihistamines, antipyretics, alpha-adrenergicagnoist, alpha-blockers, biocides, bactericides, bronchial dilators,beta-adrenergic stimulators, beta-adrenergic blocking drugs,contraceptives, cardiovascular drugs, calcium channel inhibitors,depressants, diagnostics, diuretics, electrolytes, hypnotics, hormonals,hyperglycemics, muscle contractants, muscle relaxants, opthalmics,psychic energizers, parasympathomimetics, sedatives, sympathomimetics,tranquilizers, urinary tract drugs, vaginal drugs, vitamins, calciumchannel blockers, and the like.

Exemplary drugs that can be delivered by fast drug releasing lamina 16,and by slow drug releasing lamina 17 of dosage form 10 are drugs thatare very soluble in aqueous fluids such as prochlorperazine edisylate,ferrous sulfate, aminocaproic acid, potassium chloride, mecamylaminehydrochloride, procainamide hydrochloride, amphetamine sulfate,benzphetamine hydrochloride, isoproteronol sulfate, methamphetaminehydrochloride, phenmetrazine hydrochloride, bethanechol chloride,methacholine chloride, pilocarpine hydrochloride, atropine sulfate,scopolamine bromide, isopropamide iodine, tridihexethyl chloride,phenformin hydrochloride, methylphenidate hydrochloride, cimetidinehydrochloride theophylline cholinate, cephalexin hydrochloride, and thelike.

Exemplary drugs that can be delivered by fast drug releasing lamina 16and by slow drug releasing lamina 17 of dosage form 10 are drugs thatare poorly soluble in aqueous fluids such as diphenidol, meclizinehydrochloride, prochlorperazinemaleate, phenoxybenzamine,thiethylperazine maleate, anisindone, diphenadione, erythrityltetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide,bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate,phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetylsulfisoxazole, erythromycin, progestins, esterogenic, progestational,corticosteroids, hydrocortisone, hydrocorticosterone acetate, cortisoneacetate, triamcinolone, methyltesterone, 17-beta-estradiol, ethinylestradiol, prazosin hydrochloride, ethinyl estradiol 3-methyl ether,pednisolone, 17-alpha-hydrocyprogesterone acetae, 19-norprogesterone,norgestrel, norethindrone, progesterone, norgesterone, norethynodrel,and the like.

Examples of other drugs that can be delivered by lamina 16 and lamina 17of dosage form 10 include aspirin, indomethacin, naproxen, fenoprofen,sulindac, indoprofen, nitroglycerin, propranolol, timolol, atenolol,alprenolol, cimetidine, clonidine, imipramine, levodopa,chloropromazine, methyldopa, dihydroxyphenylalnine, pivaloyloxyethylester of alpha-methyldopa, theophylline, calcium gluconate, ketoprofen,ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrouslactate, vincamine, diazepam, captopril, phenoxybenzamine, nifedipine,diltiazem, verapamil, milrinone, madol, quanbenz, hydrochlorothiazide,and the like. The beneficial drugs are known to the art inPharmaceutical Sciences, 14th Ed., edited by Remington, (1979) publishedby Mack Publishing Co., Easton, Pa.; The Drug, The Nurse, The Patient,Including Current Drug Handbook, by Falconer et al., (1974-1976)published by Sunder Co., Philadelphia, Pa.; Medicinal Chemistry, 3rdEd., Vol. 1 and 2, by Burger, published by Wiley Interscience, New Yorkand in Physicians'Desk Reference, 38th Ed., (1984) published by MedicalEconomics Co., Oradell, N.J.

The drug in dosage form 10 in lamina 16 and in lamina 17 can be invarious forms, such as uncharged molecules, molecular complexes,pharmacologically acceptable salts such as hydrochloride, hydrobromidesulfate, laurate, palmitate, phosphate, nitrite, borate, acetate,maleate, tartrate, oleate, and salicylate. For acidic drugs, salts ofmetals, amines or organic cations; for example, quaternary ammonium canbe used. Derivatives of drugs such as ester, ethers and amides can beused. Also, a drug that is water insoluble can be used in a form that isa water soluble derivative thereof to serve as a solute, and on itsrelease from the device is converted by enzymes, hydrolyzed by body pHor other metabolic processes to the original biologically active form.

The solubility of a beneficial agent including a drug can be determinedby known techniques. One method for ascertaining the solubility of anagent consists of preparing a saturated solution comprising the fluidplus the agent as ascertained by analyzing the amount of agent presentin a definite quantity of the fluid. A simple apparatus for this purposeconsists of a test tube of medium size fastened upright in a water bathmaintained at a constant temperature and pressure, in which the fluidand agent are placed and stirred by a rotating glass spiral. After agiven period of stirring, a weight of the fluid is analyzed and thestirring continued an additional period of time. If the analysis showsno increase of dissolved agent after successive periods of stirring, inthe presence of excess solid agent in the fluid, the solution issaturated and the results are taken as the solubility of the product inthe fluid. If the agent is soluble, an added osmotically effectivecompound optionally may not be needed; if the agent has limitedsolubility in the fluid, then an osmotically effective compound can beincorporated into the device numerous other methods are available forthe determination of the solubility of an agent in a fluid. Typicalmethods used for the measurement of solubility are chemical andelectrical conductivity. Details of various methods for determiningsolubilities are described in United States Public Health ServiceBulletin, No. 67 of the Hygenic Laboratory; Encyclopedia of Science andTechnology, Vol. 12, pp 542-556, (1971) published by McGraw-Hill, Inc.;and Encyclopedia Dictionary of Physics, Vol. 6, pp 547-557, (1962)published by Pergamon Press, Inc.

A drug can be present in lamina 16 and in lamina 17 neat or, in apreferred optional embodiment, with a binder, wetting agent, lubricant,dye or other lamina forming components. Representative binders includepolyvinyl pyrrolidone, lightly cross-linked polyvinyl pyrrolidone, andthe like; lubricants such as magnesium stearate and the like; wettingagents such as fatty amines, fatty quaternary ammonium salts, esters ofsorbitol, and the like.

The phrase, "drug formulation" indicates the drug is present in lamina16 and in lamina 17 neat, or accompanied by a binder, and the like.Lamina 16 and lamina 17 comprise a dosage unit amount of drug forperforming a therapeutic program, that is, for producing a therapeuticeffect. The amount of drug in lamina 16 or in lamina 17 generally isfrom about 0.05 ng to 5 g or more, with individual lamina comprising,for example, 25 ng, 1 mg, 5 mg, 10 mg, 25 mg, 100 mg, 125 mg 250 mg, 750mg, 1.0 g, 1.2 g, 1.5 g, and the like. In a presently preferredembodiment slow releasing lamina 17 comprises more drug than does fastreleasing lamina 16. Generally the amount of drug in lamina 16 to lamina17 will be in the ratio of 1:1 to 1:15. The dosage form can beadministered once, twice or three times daily.

The expression, "passageway 13" as used herein denotes an exit means inwall 12 that connects the exterior of dosage form 10 with the insidecompartment 15. Exit passageway 13 is a means for releasing fast lamina16 and slow lamina 17 to the environment of use. Dosage form 10 in onemanufacture comprises a single exit passageway. In this manufacture fastlamina 16 is dispensed from the dosage form followed by slow lamina 17through the same passageway from the dosage form. In anothermanufacture, dosgae form 10 comprises two passageway, one facing fastlamina 16 and another facing slow lamina 17. In this manufacture, lamina16 and lamina 17 are dispensed through their respective passageways.Exit means 13 dispenses fast releasing lamina 16 in a period of timefrom greater than 1 minute to 2 hours. Exit passageway 13 is shaped andsized for delivering lamina 16 in a short period of time. Exitpassageway 13 can embrace any quick-releasing shape, such asquadrilateral, rectangular, parallelogram, square, pentagonal,hexagonal, and like shape. In one embodiment exit passageway 13 cancomprise a slit of from 0.25 cm to 2.0 cm in length and from 0.20 cm to1.25 cm in width, and the like. Exit means 13 can be made by mechanicaldrilling, laser drilling, cutting the wall, and the like. The dimens1onsof exit passageway 13 for releasing the fast lamina 16 in a given timeperiod can be ascertained by manufacturing dosgae form 10 according tothe mode and manner of the invention and measuring the release thereofover time by conventional assay techniques. The slow release of lamina17 is effected by regulating the mass per unit volume of lamina 17, forexample, by using hydrogels of increasing molecular weights. Proceduresfor determining release rates are taught in Pharmaceutical Sciences, byRemington, (1970) Part V, Chapter 36, "Testing and Analysis"; Chapter37, "Analysis of Medicinals"; Chapter 38, "Biological Testing"; Chapter39, "Clinical Analysis"; Chapter 40, "Chromatograph"and Chapter 41,"Instrumental Methods of Analysis"; published by Mack PublishingCompany, Easton Pa.

Dosage form 10, in one presently preferred manufacture, is manufacturedby first making independently lamina 16, or lamina 17, which laminae aremade from a well mixed composition of laminae forming members. Forexample, a particular lamina is made as follows: first, each of theingredients comprising a lamina are independently screened and thenblended together, except for the lubricant. Then the homogeneous blendis wet granulated by adding a solvent such as anhydrous ethanol, and thewet ingredients mixed until a uniform blend is obtained by said process.Next, the wet blend is passed through a screen and dried to evaporatethe solvent. The resulting granules are passed again through a sieve.Next, a small amount of a finely divided lubricant is added to the drygranules and the lubricant and granules blended to provide a uniformblend. Next, the above described procedure is repeated for the otherlamina.

Next, the two lamina forming compositions are fed independently intoseparate hoppers of a compression machine. The machine lightlycompresses one lamina and then adds the second lamina forminggranulation in laminating arrangement to the first lamina and thencompresses the two laminae together. Typically, about two tons ofpressure are applied to laminate the laminae and yield the final dosageform.

In another manufacture the dosage form 10 can be made by a drygranulation process of manufacture. The dry process comprises firstmixing, for a particular lamina, all the lamina forming ingredients,except for the lubricant, passing the mixed ingredients through agrinding mill to a small mesh size, and then transferring the sizedpowder to a dry compactor. The compactor densifies the powder, whichdense powder is then passed through a sizing mill to regrind thecomposition. The composition is ground to a small size, typically 20mesh or smaller. Finally, a dry lubricant is added and the ingredientsblended to produce the final lamina forming composition. The secondlamina is made in a similar manner. Then, each composition is fedindependently to the compaction press and compressed into the dosageform comprising parallel laminae.

Other standard manufacturing procedures can be used to form the laminaeand the laminated dosage form. For example, the various ingredients canbe mixed with a solvent by ballmilling, calendering, stirring orrollmilling, and then pressed into a preselected sized and shapedlamina. A second lamina made in a like process comprising a shape andsize corresponding to the first lamina is then laminated with pressureto the first lamina to yield this structure of the dosage form.

Wall 12 can be applied around the slow releasing lamina and the fastreleasing lamina by molding, spraying, or dipping the pressed laminaeinto the wall forming composition. Another and presently preferredtechnique that can be used for applying the wall is the air suspensionprocedure. This procedure consists in suspending and tumbling thepressed compositions in a current of air and a wall forming compositionuntil the wall surrounds and coats the two pressed together laminae. Theair suspension procedure is well suited for independently forming thewall. The air suspension procedure is described in U. S. Pat. No.2,799,241; in J. Am. Pharm. Assoc., Vol. 48, pp 451-459 (1959) and ibid,Vol. 49, pp 82-84, (1960). A dosage forming system can be coated alsowith a wall forming composition with a Wurster® air suspension coaterusing organic solvents such a methylene dichloride/ methanol cosolvent,80/20 wt/wt, using 2.5% to 4% solids. The Aeromatic® air suspensioncoater using a methylene dichloride/methanol cosolvent, 87/13 wt/wt,also can be used for applying the wall of the lamina. Other wall formingtechniques such as pan coating can be used for applying the wall. In thepan coating system a wall forming composition is deposited by successivespraying of the compositions on the drug accompanied by tumbling thecompressed fast and slow releasing laminate in a rotating pan. A pancoater is used, in one manufacture, to produce a thicker wall. A largervolume of methanol can be used in a cosolvent to produce a thinner wall.Finally, the wall or lamina coated laminae are dried in a forced airoven at 50° C. for one to seven days to free the dosage form of solvent.Generally, the wall formed by these techniques will have a thickness of2 to 20 mils, with a presently preferred thickness of 4 to 10 mils.

Exemplary solvents suitable for anufacturing the lamina includeinorganic and organic solvents that do not adversely harm the lamina,the lamina forming ingredients and the final dosage form. The solventsbroadly include a member selected from the group consisting of alcohols,ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents,cycloaliphatic solvents, aromatic, heterocyclic solvents, and mixturesthereof. Typical solvents include acetone, diacetone, methanol, ethanol,isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate,isopropyl acetate, n-butylacetate, methyl isobutyl ketone, methyl propylketone, n-hexane, n-heptane, methylene dichloride, ethylene dichloride,propylene dichloride, ethyl ether, mixtures such as acetone and ethanol,acetone and water, acetone and methanol, methylene dichloride andmethanol, ethylene dichloride and methanol, and the like.

The following examples illustrate means and methods for carrying out thepresent invention. The examples are merely illustrative and they shouldnot be considered as limiting the scope of the invention, as theseexamples and other equivalents thereof will be come more apparent tothose versed in the pharmaceutical dispensing art in the light of thepresent disclosure, the drawings and the accompanying claims.

EXAMPLE 1

A dosage form for the controlled delivery of the beneficial drugacetaminophen is made as follows: First, a slow acetaminophen releasinglamina is prepared by blending 19.375 g of acetaminophen, 1.625 g ofhydroxypropylmethylcellulose having a molecular weight of 9,200, 2.875 gof lightly cross-linked sodium carboxymethylcellulose, and 1 g ofpolyvinylpyrrolidone in a V-blender for 20 to 25 minutes. Then, thehomogeneous blend is transferred to a beaker and 10 ml of absoluteethanol is added to the blend and the mixing continued for an additionalten minutes. The wet blend is passed through a number 20 mesh screen toproduce wet granules. The granules are dried at room temperature for 16hours, and then passed through a 20 mesh screen. Next, the granules arelubricated with 0.125 g of magnesium stearate in a Vblender for 3minutes.

Next, a fast releasing acetaminophen lamina is made by intimatelyblending 18.125 g of acetaminophen, 6.25 g of hydroxypropylcelluloseexhibiting a hydroxypropoxy content of 10% to 13%, and 0.5 g ofpolyvinylpyrrolidone are blended for 20 minutes and then transferred toa beaker. Then, 10 ml of absolute alcohol is added to the blend and theblending continued for about 10 minutes. The wet blend then is passedthrough a 20 mesh screen and allowed to dry for 16 hours at roomtemperature. The dry blend is again screened through a 20 mesh screen.The dry granules are placed in a V-blender and blended with 0.125 g ofmagnesium stearate for 3 minutes.

Next, 451.6 mg of the slow drug releasing formulation is pressed into a7/10" oval shape on a Manesty® layer press and 206.9 mg of the fastreleasing drug layer is pressed on top of the slow releasing layer toprovide a bilayer drug core.

Next, the bilamina is surrounded with a semipermeable wall. Thesemipermeable wall forming composition comprises 80% cellulose acetatehaving an acetyl content of 39.8%, 10% hydroxypropylmethylcellulosehaving a molecular weight of 11,300 (HPMC E-5), and 10% polyethyleneglycol. The semipermeable wall is applied in an Aeromatic® airsuspension coater. A coating solution comprising the cellulose acetate,hydroxypropylmethylcellulose and the polyethylene glycol dissolved inmethylene chloride-methanol, 90:10 wt %, to give 4% solids, is sprayedaround the bilamina to provide the wall. Next, the semipermeable wallcoated dosage forms are dried in a forced air oven for 16 hours at 50°C. to evaporate the solvents.

Next, the dried dosage forms are divided into two groups. One group isdrilled with a 50 mm orifice on two faces of the dosage form. The othergroup is drilled with a 20 mil wide by 197 mil long slit on each face.Then, both groups of dosage forms are placed in artificial gastric fluidand artificial intestinal fluid at 37° C. and the release rateascertained in a USP release rate tester. The release rates for thedosage forms with the two orifices is seen in FIG. 3. In FIG. 3 dosageform 10 comprises two 50 mil passageways. The release rate curve withthe connecting squares denotes measurements made in artificialintestinal fluid and the release rate curve connected with plus marksdenotes measurement made in artificial gastric fluid. In FIG. 4, thedosage form comprises two 0.5 cm slits. In FIG. 4 the release rate curvewith the connecting squares denotes measurements made in artificialintestinal fluid, and the release rate curve connected by plus signsdenotes the release rate measured in artificial gastric fluid.

EXAMPLE 2

A dosage form for delivering a beneficial drug to an environment of useis prepared as follows: A slow drug releasing lamina is fluid bedgranulated in a Vector Freund Flo-Coater. The slow drug releasing laminais prepared as follows: First, 22.25 kg of acetaminophen and 6.0 kg ofpolyethylene oxide having a molecular weight of 200,000 are placed inthe bowl of the fluid bed granulator. Then, while the powders aremixing, 30 kg of a solution of of 5% hydroxypropylmethylcelluloseexhibiting a molecular weight of 11,300 in distilled water is sprayedonto the ingredients to form a granulation. Then, 150 g of magnesiumstearate is added to the granulation in a Rotocone® blender and mixingcontinued for 5 minutes. The granulation's final composition comprises74.5% acetaminophen, 20% polyethylene oxide, 5%hydroxypropylmethylcellulose and 0.5% magnesium stearate.

Next, a fast drug releasing layer is prepared as follows. 23.25 kg ofacetaminophen, 2.1 kg of hydroxypropylcellulose exhibiting ahydroxypropoxy content of 10% to 13%, 3 kg of sodium bicarbonate and0.09 kg of ferric oxide are placed in a granulator bowl of aVectorFreund Flocoater. While the ingredients are mixing in thegranulator, 30 kg of a 5% hydroxypropylmethyl cellulose, having anaverage molecular weight of 11,300-E5, in water is sprayed onto thepowder to form granules. The granules then are lubricated with 154.7 gof magnesium stearate for 5 minutes in a Rotocone blender. The finalcomposition prepared by the granulation comprises 77.3% acetaminophen,10% sodium bicarbonate, 7% hydroxypropylcellulose, 5%hydroxypropylmethylcellulose. 0.5% magnesium stearate and 0.3% ferricoxide.

The two lamina forming compositions were compressed into a bilaminateusing a Manesty® press. First, 469.8 mg of the slow formulation is addedto the Manesty press and pressed to form a lamina. Then, 194.1 mg of thefast formulation is added to the Manesty press and pressed to form afast releasing lamina in contact with the slow releasing lamina.

Next, the bilaminate is coated with a semipermeable wall. Thesemipermeable wall weighs 35.2 mg and comprises 70% cellulose acetaehaving an acetyl content of 39.8%, 15% polyethylene glycol 3350, and 15%hydroxypropylmethylcellulose having a number average molecular weight of11,300. The semipermeable wall is applied in an AccelaCota® rotatingopen coater. The coating solution consists of the cellulose acetate, thepolyethylene glycol and the hydroxypropylmethylcellulose dissolved inmethylene chloride:methanol, (90:10 wt %) to give a 4% solution.

After drying a slit passageway is formed in the wall using a lasergenerator. First a slit is laser drilled through the wall to connect thefast releasing lamina with the exterior of the dosage form. Then thedosage form is turned over and a laser slit passageway is drilledthrough the wall to the slow releasing lamina.

The release of drug from the dosage form is measured in artificialgastric fluid. The cumulative release rate is depicted in FIG. 5.

EXAMPLE 3

The procedure of example 2 is followed in preparing this example. Thedosage form prepared in this example comprises (1) a fast dissolvinglamina comprising 77.5% acetaminophen, 10% sodium bicarbonate, 7%hydroxypropylcellulose, 5% hydroxypropylmethylcellulose having amolecular weight of 11,300, and 0.5% magnesium stearate, (2) a slowreleasing lamina comprising 74.5% acetaminophen, 20% polyethylene oxidehaving a molecular weight of 200,000 and 5% hydroxypropylmethylcellulosehaving a molecular weight of 11,300 and 0.5% magnesium stearate, and (3)a wall comprising 70% cellulose acetate having an acetyl content of39.8%, 15% hydroxypropylmethylcellulose having a molecular weight of11,300 and 15% polyethylene glycol 3350. In this example cumulativerelease rates are measured for dosage forms with different slitpassageways are plotted in FIG. 6, the line connected through squaresindicates the cumulative amount released for a dosage form comprisingtwo slit passageways measuring 1.25 cm ×0.0007 cm; the line connected byplus signs denotes a dosage form comprising two slits of 1.25 cm×0.03cm; the line connected by diamonds indicates a dosage form with one slit1 cm ×0.07 cm, and the line connected through triangles denotes a dosageform with a single slit passageway 1.5 cm ×0.04 cm. In one preferredembodiment the passageway exhibits an area of 0.20 to 0.40 cm².

EXAMPLE 4

This example illustrates the effect of the weight of the wall on thecumulative amount released from a dosage form. In accompanying FIG. 7,the cumulative amount of acetaminophen released from a dosage formcomprising a single passageway, a slow releasing lamina and a fastreleasing lamina are llustrated as follows: the line connected withsquares indicates the amount released from a dosage form with a wallweighing 13.1 mg, the lines connected by plus signs indicate the amountreleased when the wall weighs 77 mg, the line with triangles indicatesthe amount released when the wall weighs 25 mg, and line with ×'sindicates the cumulative amount released when the wall weighs 31 mg.

EXAMPLE 5

This example illustrates the release rate of dosage forms wherein theslow releasing lamina comprises different components. The fast releasinglamina of the dosage form comprises 80.0% phenylpropanolhydrochloride(PPA +Cl), 10% hydroxypropylcellulose, 5% sodium bicarbonate and 4.75%hydroxypropylmethylcellulose having a molecular weight of 11,300 and0.25% magnesium stearate. The fast releasing lamina is used in twodosage forms comprising different slow releasing lamina. The slowreleasing laminae are (a) a slow releasing lamina comprising 10%hydroxypropylmethylcellulose having a molecular weight of 9,200, 4%hydroxypropylmethylcellulose having a molecular weight of 241,900, 3%hydroxypropylcellulose, 2% hydroxypropylmethylcellulose having amolecular weight of 11,300, 80.5% PPAHCl and 0.5% magnesium stearate;and (b) a slow releasing lamina comprising 4%hydroxypropylmethylcellulose having a molecular weight of 241,900, 3%hydroxypropylcellulose, 12% hydroxypropylmethylcellulose having amolecular weight of 11,300, 80.5% PPAHCl and 0.5% of magnesium stearate.The slow releasing lamina weight is 62.11 mg and the fast releasinglamina weight if 31.25 mg. The fast and slow releasing bilaminate issurrounded by a wall with a slit passageway on each face. The fastreleasing lamina releases 25 mg of PPAHCl in a short period and the slowreleasing lamina releases 50 mg of PPAHCl over a prolonged period.

An embodiment of the invention pertains to administering a beneficialdrug to an animal, such as a human. The method for administering abeneficial drug at a controlled rate comprises the steps of: (A)admitting into an animal a dosage form comprising (1) a wall comprisingat least in part a semipermeable polymeric composition permeable to thepassage of fluid and substantially impermeable to the passage of drug,the wall surrounding (2) an internal lumen; (3) a fast dissolving laminain the lumen that is delivered form the dosage form in from 1 minute to2 hours; (4) a slow releasing lamina in the lumen that is delivered fromthe dosage form in from 11/2 hours to 24 hours; (5) a drug in the fastreleasing lamina; (6) a drug in the slow releasing lamina, said drug thesame or a different drug than in the fast releasing lamina; (7) exitmeans through the wall connecting the fast releasing lamina with theexterior of the dosage form, said exit means sized for delivering thefast releasing lamina from the dosage form in from 1 minute to 2 hours,(B) imbibing fluid through the semipermeable wall into each lamina at arate determined by the permeability of the semipermeable wall and theosmotic pressure gradient across the wall to continuously change thelamina into a dispensable formulation; and, delivering the lamina underhydrostatic pressure from the dosage form to the animal foradministering the drug to produce therapeutic result.

The novel dosage form of this invention comprises means for theobtainment of precise release rate in the environment of use whilesimultaneously providing beneficial therapy to a recipient. Where therehas been described and pointed out features of the invention as appliedto presently preferred embodiments, those skilled in the dispensing artwill appreciate that various modifications, changes, additions andomissions in the dosage form illustrated and described can be madewithout departing from the spirit of this invention.

We claim:
 1. A dosage form for delivesring a drug to an animal, whereinthe dosage form comprises:(a) a wall comprising at least in part acomposition permeable to fluid; (b) a compartment desfined by the wall;(c) a first composition in the compartment comprising (1) atherapeutically effective amount of acetaminophen, and (2) ahydroxypropylcellulose comprising about 17% to 16% hydroxypropyl group;(d) a second composition in the compartment comprising (3) atherapeutically effective amount of acetaminophen, and (4)a memberselected from the group consisting of a hydroxypropylmethylcellulose anda hydrogel; and, (e) exit means frod elivering the first composition ina short period of time.
 2. A dosage form for delivering a drug orally toan animal, wherein the dosage form comprises:(a) a wall comprising atlease in part a compostion permeable to fluid; (b) a compartment formedby the wall; (c) a first composition in the compartment comprising (1) atherapeutically effective amount of phenylpropanolamine and (2) ahydroxypropylcellulose comprising about 7% to 16% hydroxypropyl group;p1 (d) a second composition in the compartment comprising (3) atherapeutically effective amount of phenylpsropanolamine and (4) amember selected from the group consisting of ahydroxypropylmethylcellulose and a hydrogel; and, (e) exit means fordelivering the first composition in a short period of time.